PARP-1, the principal member of the growing family of Poly(ADP-ribose)polymerases, plays a fundamental role in the preservation of genomic integrity. Activation of DNA-damaging pathways following CNS injuries is one of the causes of PARP-1 overactivation which may results, through depletion of the NAD reservoir, in neuronal death [1]. A sustained therapeutical potential is therefore associated with inhibition of PARP-1 in those disorders and diseases characterized by massive DNA-damage. In particular, the efficacy of PARP-1 inhibitors has been assessed in several animal models of brain ischemia [2] and this justifies the continuous search for more potent, selective and bioavailable inhibitors.An essential prerequisite for the rational design and ADME optimization of novel inhibitors is detailed information about the active site structure and reaction mechanism. In this communication we report a computational chemistry study finalized at the understanding of the structural requirements for potent PARP-1 inhibition. In particular, the importance of desolvatation, hydrophobic and aromatic-aromatic interactions, and electrostatic potential will be evaluated for selected classes of potent PARP-1 inhibitors. Furthermore, the issue of selectivity will be addressed by comparison of the crystallographic structures of the catalytic fragment of PARP-1 and PARP-2.

Keywords: PARP-1 inhibitors, molecular modeling, active site